This is an application to establish a Brittle Bones Disorders Rare Disease Clinical Research Consortium (BBD RDCRC) focused on studying the over 13 genetic conditions that not contribute to the Osteogenesis Imperfecta (OI) phenotype. The BBD RDCRC is composed of 8 primary clinical sites (Houston, Los Angeles, Portland, Chicago, Montreal, New York City, Baltimore, Washington DC), 2 core sites (Seattle and Tampa), one training & advocacy site (Osteogenesis Imperfecta Foundation), and an Administrative unit (Houston). We propose two clinical projects. Project 1 is a Longitudial study of OI focused on correlating genotype to phenotype, natural history of vertebral fractures in OI type I, scoliosis in severe OI, pregnancy i OI, and craniofacial/dental features in severe Ol. Project 2 is a Phase I trial of an anti-TGFb therapy Fresolimumab in severe OI in the context of a dose ranging study followed by an extension repeat dosing study. There will be two Pilot Projects. The first focuses on the development of mass spectrometric analysis of urinary collagen cross-link patterns as a tool for distinguishing different mechanistic causes of Ol and for correlating with disease severity. The second focuses on validating aspects of the PROMIS tool for adults with OI. An important partner will be the Osteogenesis Imperfecta Foundation (OIF) and the Training and Advocacy activities will be coordianted by the OIF. They include establishment of a new fellowship for clinical research training, a clinical bone research training workshop, and development of a tool box of web-based training for primary healthcare providers to extend the knowledge gained by these studies to patients. Finally, the administration of the BBD RDCRC will be based in Houston at the Baylor College of Medicine. The BBD RDCRC will be leveraged by resources from the OIF who will directly support two of the clinical sites and a pilot project on PROMIS, the Shriners Hospital system, and institutional commitments from Baylor College of Medicine. The BBD RDCRC is built on established cohorts of the OIF Linked Longitudinal Clinical Research Centers and established expertise in pediatric and adult interventional studies that demonstrates a track record of success in patient advocacy, recruitment, and retention for clinical research studies.